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The Capital Region of Denmark - a part of Copenhagen University Hospital
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High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer

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  1. The global dissemination of hospital clones of Enterococcus faecium

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  2. Trans-ethnic gut microbial signatures of prediabetic subjects from India and Denmark

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  3. Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India

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  4. Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

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  5. Elevated polygenic burden for autism is associated with differential DNA methylation at birth

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  1. Basal Cell Carcinoma of Prostate With MSMB-NCOA4 Fusion and a Probable Basal Cell Carcinoma In Situ: Case Report

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  2. Genomic Alterations in Human Papillomavirus-Positive and -Negative Conjunctival Squamous Cell Carcinomas

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  3. The collagen receptor uparap in malignant mesothelioma: A potential diagnostic marker and therapeutic target

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  4. Danish guidelines for management of non-APC-associated hereditary polyposis syndromes

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  5. Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

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Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.

Original languageEnglish
Article number13
JournalGenome Medicine
Volume4
Issue number1
Pages (from-to)13
ISSN1756-994X
DOIs
Publication statusPublished - 2019

ID: 58596959